Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to determine whether neurotensin acts within the arcuate nucleus/median eminence to activate tyrosine hydroxylase (TH) within tuberoinfundibular dopamine neurons. The role of Ca2+/phospholipid-dependent protein kinase (protein kinase-C) in the regulation of TH and its involvement in the neurotensin-induced activation of TH within tuberoinfundibular dopamine (TIDA) neurons also was investigated. The activity of TH within TIDA neurons was assessed by quantification of the formation of 3,4-dihydroxyphenylalanine in the arcuate nucleus/median eminence after inhibition of 3,4-dihydroxyphenylalanine decarboxylase. Neurotensin (0.1-10 nM) increased the activity of TH within the arcuate nucleus/median eminence under in vitro conditions by approximately 80%. The activity of TH in the arcuate nucleus/median eminence also was increased approximately 55% by the phorbol ester 12-O-tetradecanoyl(phorbol-13-acetate) (1-100 nM), which activates protein kinase-C. Sphingosine (10 microM), an inhibitor of protein kinase-C, attenuated the activation of TH within TIDA neurons that was induced by both 12-O-tetradecanoyl(phorbol-13-acetate) and neurotensin. Sphingosine alone did not alter the activity of TH, nor did it alter the (Bu)2cAMP-induced activation of TH in the arcuate nucleus/median eminence. It is concluded that neurotensin acts directly within the arcuate nucleus/median eminence to activate TIDA neurons. Furthermore, it is suggested that the activity of TH within these neurons is enhanced after the activation of protein kinase-C and that protein kinase-C may mediate the neurotensin-induced activation of TH within these hypothalamic dopamine neurons.
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PMID:Evidence for protein kinase-C mediation of the neurotensin-induced activation of tyrosine hydroxylase in tuberoinfundibular dopaminergic neurons. 135 1

Sphingosine displays multiple biochemical and biological effects, in particular inhibition and activation of protein kinases. To determine the predominant interaction of sphingosine with cellular kinases, the effects of sphingosine on endogenous protein phosphorylation in Jurkat T lymphoblastic cells were investigated in vitro. Sphingosine was found to cause prominent phosphorylation of a number of cytosolic proteins ranging in molecular mass from 18 to 165 kDa. Phosphorylation was calcium-independent. Phosphorylation of substrates was increased in response to concentrations of sphingosine as low as 10 microM and peaked at concentrations of 20-200 microM. Multiple lines of evidence suggested that sphingosine activated more than one protein kinase: 1) the concentration dependence on sphingosine differed from substrate to substrate, 2) phosphorylation of one group of substrates required ATP as the phosphate donor, whereas a second group showed no preference between ATP and GTP, and 3) phosphorylation of some substrates was inhibited by heparin, whereas other substrates were resistant. Activation of these kinases demonstrated a very specific requirement for D-erythro-sphingoid bases. DL-erythro-dihydrosphingosine was partially active, whereas DL-threo-dihydrosphingosine was not. Other related molecules such as stearylamine, sphingomyelin, and C2-ceramide were not active. Sphingosine-activated kinase(s) were distinct from protein kinase C, cyclic nucleotide-activated kinases, and calcium-dependent kinases. These observations demonstrate the existence of multiple sphingosine-activated protein kinases with high specificity for D-erythro-sphingosine, suggesting physiologic regulation of protein phosphorylation by sphingosine.
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PMID:Sphingosine activation of protein kinases in Jurkat T cells. In vitro phosphorylation of endogenous protein substrates and specificity of action. 163 54

Sphingosine activates casein kinase II in the presence of endogenous substrates as well as a synthetic peptide substrate. The activation response occurred between 12 and 25 micrograms/ml sphingosine and exhibited positive cooperativity with a Hill coefficient of 3.0. Sphingosine not only increased the Vmax of casein kinase II but decreased the Km(app) for the peptide substrate from 0.5 to 0.08 mM. In contrast, the Km(app) for MgCl2 was increased from 0.12 to 0.7 mM. Consequently, sphingosine altered significantly several parameters which determine casein kinase II activity. The effect of sphingosine was relatively specific, inasmuch as related lipids were less potent activators or largely ineffective in stimulating casein kinase II. On the other hand, the effect of sphingosine itself could be potentiated or inhibited by other lipids. Ceramide and sphingosylphosphorylcholine augmented the sphingosine effect. Phospholipids alone did not alter the activity of casein kinase II significantly, but abolished enzyme activation by sphingosine with different potencies (phosphatidylserine greater than phosphatidylethanolamine greater than phosphatidylinositol greater than phosphatidylcholine). Moreover, the sphingosine effect could be abrogated by KCI and NaCl, which alone are known to induce enzyme activation and dissociation of aggregated casein kinase II protein; LiCl and NH4Cl also inhibited the sphingosine effect. Polyamines, known activators of casein kinase II, partially mimicked the effect of sphingosine on endogenous polypeptide phosphorylation but failed to do so with the peptide substrate. These observations demonstrate that sphingosine is a potent activator of casein kinase II. The potential pharmacological and physiological modulation of casein kinase II by sphingoid bases is discussed.
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PMID:Activation of casein kinase II by sphingosine. 193

Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.
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PMID:Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. 194 18

As a measure of the transmembrane signals that they transduce, two neurotrophic agents, nerve growth factor (NGF) and basic fibroblast growth factor (bFGF), and the muscarinic agonist carbachol were compared for their ability to induce TIS (tetradecanoyl phorbol acetate-inducible sequences) transcripts, representing a family of immediate early response genes, in the rat pheochromocytoma cell line PC12 and the morphologically unresponsive variant PC12nnr5. Three genes, TIS1 (also designated NGFIB), TIS8 (also designated NGFIA), and TIS21, induced in these cells by NGF (Kujubu, D.A., Lim, R.W., Varnum, B.C., and Herschman, H.R. (1987) Oncogene 1, 257-262, 1987), are also induced by bFGF and carbachol. In native PC12 cells the level of expression of TIS8 and TIS21 is similar for all three stimuli, as well as for tetradecanoyl phorbol acetate (TPA). In contrast, the induction of TIS1 by NGF and TPA is slight and is only just detectable after stimulation by bFGF, but is strong for carbachol. Thus, although all of these agents can stimulate protein kinase (PK-C), at least one TIS gene can apparently be differentially regulated by these ligands, suggesting that alternative signaling pathways must also exist. In keeping with this view, bFGF, and to a lesser degree NGF, can elicit a TIS gene response in PC12 cells in which PK-C has been down-regulated with TPA. The response to carbachol (and TPA) is effectively blocked under these conditions. Since both NGF and bFGF stimulate neurite outgrowth in such cells, PK-C is apparently not essential, i.e. does not represent the sole mechanism, for signal transduction leading to modulation of gene expression for these factors. Consistent with this model, putative protein kinase inhibitors, K252a and sphingosine, did not inhibit the TIS gene responses to bFGF. However, these agents also failed to block TIS gene responses to carbachol and TPA indicating that they were ineffective as PK-C inhibitors under these conditions. The NGF-induced response was, however, blocked by K252a indicating a unique step in the mechanism of this factor not shared by the other ligands. Sphingosine did not block TIS induction with NGF. The mutant cell line PC12 nnr5 does not respond morphologically to either NGF or bFGF. However, TIS gene responses to bFGF are unaffected, whereas those to NGF are completely abolished. The response to TPA is altered quantitatively but not qualitatively; the induction by carbachol is largely eliminated, apparently as a result of a 90% reduction in muscarinic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential induction of primary-response (TIS) genes in PC12 pheochromocytoma cells and the unresponsive variant PC12nnr5. 200 87

Sphingosine inhibition of [3H] [N3-Me-His] TRH (MeTRH) binding, previously shown to be independent of its effects on protein kinase-C, has been further characterized in GH3 cell membranes and in a partially purified, digitonin-solubilized receptor preparation. In membranes, as in intact cells, sphingosine inhibited [3H]MeTRH binding by decreasing receptor affinity, but, in contrast to its effect in intact cells, did not affect the number of available binding sites. The inhibition of binding was linear up to 75 microM sphingosine (in the presence of 100 microM BSA at 0.1 mg membrane protein/ml), yielding an apparent Ki of 51 microM. Since GTP decreases the affinity for MeTRH binding in GH3 cell membranes, we studied interactions between GTP and sphingosine. While the effects of low concentrations of GTP gamma S and sphingosine were additive, sphingosine inhibition of MeTRH binding surpassed and was not affected by the addition of maximally inhibitory concentrations of GTP gamma S. Also, sphingosine (75 microM) did not affect the ability of a maximally effective dose of TRH to stimulate the low Km GTPase (vehicle, +35 +/- 5%; sphingosine, +32 +/- 10%); there was a 25% decrease in total GTPase activity in the presence of sphingosine. MeTRH binding to digitonin-solubilized receptors, which had properties similar to those described previously by others, including no effect of GTP on binding, was inhibited by sphingosine. In solubilized receptors, as in membranes, sphingosine caused a decrease in apparent affinity without changes in the number of binding sites. These data suggest that sphingosine interacts directly with the TRH receptor [or an associated factor(s) in the receptor complex] to decrease affinity by a mechanism that does not involve uncoupling of G-proteins.
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PMID:Sphingosine interacts directly with the receptor complex to inhibit thyrotropin-releasing hormone binding. 210 32

The role of Ca2+/phospholipid-dependent protein kinase (protein kinase C) in catecholamine secretion from bovine adrenal medullary chromaffin cells was examined using four protein kinase C inhibitors: polymyxin B, sphingosine, staurosporine, and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). For this purpose, digitonin-permeabilized chromaffin cells were used. Secretion of catecholamines from these cells was stimulated by the addition of micromolar amounts of exogenous free Ca2+. 12-O-Tetradecanoylphorbol-13-acetate (TPA) and arachidonic acid, activators of protein kinase C, enhanced the catecholamine secretion evoked by Ca2+. But phorbol-12, 13-diacetate, a phorbol ester analog that does not activate protein kinase C, had no effect on Ca2(+)-evoked secretion. Polymyxin B at a low concentration (1 microM) abolished the enhancement of secretion by TPA or arachidonic acid without affecting the secretion evoked by Ca2+. However, polymyxin B at higher concentrations (10-100 microM) greatly reduced Ca2+-evoked catecholamine secretion. Sphingosine 10 microM-1 mM), Staurosporine (100 nM-1 microM, and H-7 (100-500 microM) inhibited TPA- or arachidonic acid-enhanced secretion but not Ca2(+)-evoked secretion. In cells in which protein kinase C was down-regulated by TPA, specific binding of [3H]phorbol-12,13-dibutyrate to the cells almost disappeared and the enhancement of secretion by TPA was no longer observed, whereas Ca2(+)-evoked secretion was maintained. These results strongly suggest that protein kinase C is not essential for the Ca2(+)-dependent catecholamine secretion from bovine adrenal chromaffin cells, but acts instead as a modulator.
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PMID:Role of Ca2+/phospholipid-dependent protein kinase in catecholamine secretion from bovine adrenal medullary chromaffin cells. 212 Nov 47

Exposure to ethanol for several days increases the expression of dihydropyridine-sensitive, voltage-dependent Ca2+ channels in brain and in the neural cell line PC12. Since protein phosphorylation is a major mechanism by which ion channels are regulated, we used protein kinase inhibitors to investigate whether ethanol-induced up-regulation of Ca2+ channels involves activation of a protein kinase. Sphingosine and polymixin B, which inhibit protein kinase C and calmodulin-dependent kinases, prevented the enhancement of 45Ca2+ uptake induced by exposure of PC12 cells to ethanol for 4 days. In addition, sphingosine blocked the ability of ethanol to increase the number of [3H]dihydropyridine binding sites in PC12 cell membranes. Sphingosine's effect was prevented by simultaneous exposure to phorbol 12,13-dibutyrate, a potent activator of protein kinase C. Therefore, protein kinase C appears to be involved in the up-regulation of dihydropyridine-sensitive Ca2+ channels during prolonged exposure to ethanol.
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PMID:Protein kinase C participates in up-regulation of dihydropyridine-sensitive calcium channels by ethanol. 216 38

We used rat proximal tubule fragments purified by Percoll centrifugation to examine the role of diacylglycerol (DAG) in noradrenergic-stimulated Na+ reabsorption. Tubular DAG concentration and ouabain-inhibitable 86Rb uptake increased within 30 s after adding norepinephrine (NE) and remained elevated for at least 5 min. NE (1 microM) increased DAG content 17% and ouabain-inhibitable 86Rb uptake 23%. Cirazoline-stimulated 86Rb uptake was not inhibited by BaCl, quinidine, or bumetanide (1-10 microM) or by the omission of HCO3- or Cl- from the medium, but it was completely inhibited by ouabain and furosemide. Oleoyl-acetyl glycerol, L-alpha-1,2-dioctanoylglycerol, and L-alpha-1,2-dioleoylglycerol (DOG) increased total 86Rb uptake 8-11%. 12-O-tetradecanoylphorbol-13-acetate (TPA) (5 nM) increased uptake by only 4%. Staurosporine at 5 nM inhibited DOG stimulation completely, whereas 50 nM staurosporine was required to inhibit NE stimulation completely. Sphingosine inhibited DOG stimulation by 66% but did not inhibit NE stimulation. Amiloride (1 mM) completely blocked DOG stimulation. Monensin increased 86Rb uptake 31% and completely blocked the DOG effect but reduced the NE effect by only 26% (P = 0.08). In tubules from salt-loaded rats, NE did not increase DAG concentration, but NE-stimulated 86Rb uptake was reduced by only 23% (P = 0.15). Thus DAG released by NE may stimulate Na+ entry through Na(+)-H+ exchange. NE predominantly stimulates Na(+)-K(+)-adenosinetriphosphatase (ATPase) by activating a protein kinase that is insensitive to DAG and TPA and is inhibited by staurosporine but not by sphingosine. NE may also stimulate K+ efflux through a BaCl-insensitive K+ channel that is inhibited by millimolar furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of diacylglycerol in adrenergic-stimulated 86Rb uptake by proximal tubules. 233 44

The role of protein kinases in renal noradrenergic stimulation was examined using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), or staurosporine to inhibit the responses to norepinephrine (NE, 60 nM) in isolated perfused rat kidneys. Sphingosine (20 mumol/L) increased the noradrenergic vasoconstrictor response. H7 (10 mumol/L) partially blocked the immediate vasoconstrictor response and completely inhibited it after 2 min without altering the antinatriuretic and antilithuretic responses. H7 also blocked the increase in free water produced by NE, which is consistent with the inhibition of protein kinase A linked to beta-adrenergic stimulation. Staurosporine (10 nmol/L) partially inhibited noradrenergic vasoconstriction and antinatriuresis, and it completely blocked the depression of gluconeogenic responses to NE in pyruvate-perfused kidneys. To examine the role of diacylglycerol and protein kinase C in the renal responses to NE, we used oleoyl-acetyl-glycerol (OAG, 50-100 microM) or phorbol-12-myristyl-13-acetate (TPA, 5-50 nM). TPA slowly vasoconstricted the kidney and reduced GFR and fractional Na+, Li+, and free water excretion. Amiloride (1 mM) prevented the TPA responses. OAG mimicked the effects of TPA except that vasoconstriction occurred more rapidly and was brief. Both TPA and OAG acted like alpha 1-adrenergic agonists. These results indicate that diaclyglycerol and protein kinase are involved in the prolonged effects of NE on vasoconstriction. GFR, and proximal tubular reabsorption.
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PMID:Diacylglycerol and protein kinase mediated noradrenergic responses in perfused rat kidneys. 239 Jul 42


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